Bilateral Striatal Lesions Research Articles

Cellular, Behavioral, and Locomotor Effects of Oral Nicotine in Male Rats with Bilateral Lesions in the Ventrolateral Striatum Induced with 6-OHDA

Objective: Parkinson's disease is a progressive neurodegenerative disease having a spectrum of non-motor to motor symptoms. Unrelated to motor symptoms of sensory, autonomic, and neuropsychiatric symptoms often appear early in the course of the disease. It is a remarkable observation that patients in the premotor phase can easily quit smoking without help. This study was intended to investigate the interrelation between nicotine and the partial loss of dopaminergic innervation in the ventrolateral striatum induced by 6-OHDA. 
 Methods: We used an experimental premotor parkinsonism model. The oral nicotine preference of rats was investigated with the two-bottle free choice method. The behaviors related to locomotor activity and emotional state were evaluated with a locomotor activity test, elevated plus maze, and forced swimming test. Histopathological evaluation was performed in the striatum by staining techniques using hematoxylin+eosin (H&E) and immunohistochemistry markers (caspase-3, and MAP-2).
 Results: Bilateral 6-OHDA lesions did not lead to a significant alteration in the total locomotor activity or nicotine preference. Nicotine increased horizontal but decreased vertical movements in addition to increasing anxiolytic but also depressive effects in the OHDA lesion group. The number of apoptotic cells was significantly lower in the lesion group receiving nicotine compared to those not receiving nicotine.
 Conclusion: Our experimental study points to the role of oral nicotine in male rats with bilateral striatal 6-OHDA lesions in the ventrolateral striatum. Further studies are needed to understand the relationship between loss of dopaminergic innervation in the striatum and nicotine consumption.

A Neuropsychiatric and Neuroimaging Study of Unilateral and Bilateral Striatal Ischemic Lesions.

Neuropsychiatric disorders after striatal territory stroke have not been studied systematically. The investigators aimed to study the spectrum of cognitive and behavioral disorders following striatal infarcts. Different aspects of cognitive functions, including executive, frontal lobe, memory, visuospatial, language, and semantic processing, were assessed among patients with striatal infarct. Structural MRI data sets were obtained 3 months after stroke to delineate affected territories of the striatum. MRIcroGL software was used to acquire multiple layers of images, generate volume renderings, and draw volumes of interest. To determine the brain locus most frequently affected in patients with distinct cognitive disorders, ischemic area distributions in patients with cognitive dysfunction versus those without cognitive impairment were contrasted. Among 60 patients in this study, six different striatal infarction types were significantly associated with seven different cognitive categories (p<0.001). Unilateral caudate lesion was characterized by attention, planning, and executive disorders (38%), and unilateral lentiform infarct was characterized by executive (36%) and frontal (36%) dysfunctions. Bilateral caudate infarcts caused impairments in frontal and executive functions (75%), as well as in autobiographical (50%) and episodic (50%) memory. In those with bilateral caudate plus lentiform infarcts, all components of frontal and executive functions were dramatically impaired. The anteromedial striatum was affected more frequently in patients with language impairment compared with patients with other types of cognitive dysfunction (p<0.001). Following striatal stroke, a wide range of frontal-like cognitive impairments occurred, along with impaired working memory, declarative memory, executive function, speech fluency, and motor function.

The pathogenic MT-ATP6 m.8851T>C mutation prevents proton movements within the n-side hydrophilic cleft of the membrane domain of ATP synthase

Dozens of pathogenic mutations have been localized in the mitochondrial gene (MT-ATP6) that encodes the subunit a of ATP synthase. The subunit a together with a ring of identical subunits c moves protons across the mitochondrial inner membrane coupled to rotation of the subunit c-ring and ATP synthesis. One of these mutations, m.8851T>C, has been associated with bilateral striatal lesions of childhood (BSLC), a group of rare neurological disorders characterized by symmetric degeneration of the corpus striatum. It converts a highly conserved tryptophan residue into arginine at position 109 of subunit a (aW109R). We previously showed that an equivalent thereof in Saccharomyces cerevisiae (aW126R) severely impairs by an unknown mechanism the functioning of ATP synthase without any visible assembly/stability defect. Herein we show that ATP synthase function was recovered to varying degree by replacing the mutant arginine residue 126 with methionine, lysine or glycine or by replacing with methionine an arginine residue present at position 169 of subunit a (aR169). In recently described atomic structures of yeast ATP synthase, aR169 is at the center of a hydrophilic cleft along which protons are transported from the subunit c-ring to the mitochondrial matrix, in the proximity of the two residues known from a long time to be essential to the activity of FO (aR176 and cE59). We provide evidence that the aW126R change is responsible for electrostatic and steric hindrance that enables aR169 to engage in a salt bridge with cE59. As a result, aR176 cannot interact properly with cE5 and ATP synthase fails to effectively move protons across the mitochondrial membrane. In addition to insight into the pathogenic mechanism induced by the m.8851T>C mutation, the present study brings interesting information about the role of specific residues of subunit a in the energy-transducing activity of ATP synthase.

Transient bilateral striatal lesion associated with varicella infection.

Transient bilateral striatal lesion associated with varicella infection.

Neurological Disorders Associated with Striatal Lesions: Classification and Diagnostic Approach.

Neostriatal abnormalities can be observed in a very large number of neurological conditions clinically dominated by the presence of movement disorders. The neuroradiological picture in some cases has been described as "bilateral striatal necrosis" (BSN). BSN represents a condition histo-pathologically defined by the involvement of the neostriata and characterized by initial swelling of putamina and caudates followed by degeneration and cellular necrosis. After the first description in 1975, numerous acquired and hereditary conditions have been associated with the presence of BSN. At the same time, a large number of disorders involving neostriata have been described as BSN, in some cases irrespective of the presence of signs of cavitation on MRI. As a consequence, the etiological spectrum and the nosographic boundaries of the syndrome have progressively become less clear. In this study, we review the clinical and radiological features of the conditions associated with MRI evidence of bilateral striatal lesions. Based on MRI findings, we have distinguished two groups of disorders: BSN and other neostriatal lesions (SL). This distinction is extremely helpful in narrowing the differential diagnosis to a small group of known conditions. The clinical picture and complementary exams will finally lead to the diagnosis. We provide an update on the etiological spectrum of BSN and propose a diagnostic flowchart for clinicians.

De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions

Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.

Reversible bilateral striatal lesions following Mycoplasma pneumoniae infection associated with elevated levels of interleukins 6 and 8

Reversible bilateral striatal necrosis associated with Mycoplasma pneumoniae (M. pneumoniae) infection is a rare neurological disease. The exact pathogenic mechanism remains unknown. We report reversible bilateral striatal lesions with a favorable outcome secondary to M. pneumoniae infection in an 8-year-old Chinese girl. Cranial MRI showed abnormal signals in bilateral striatum, which disappeared 8 months later. To better understand the pathogenesis of this encephalopathy, we examined cytokines levels in serum and cerebrospinal fluid from this patient. The results revealed the concentrations of interleukin-6 and interleukin-8 increased significantly in serum (26 pg/mL and 66 pg/mL, respectively) and cerebrospinal fluid (122 pg/mL and 325 pg/mL, respectively), and were reduced markedly after the therapy. Intrathecal production of interleukin-6 and interleukin-8 is probably related to the pathogenesis of striatal lesions caused by M. pneumoniae. These cytokines may cause local vascular injury, and finally leading to local vascular occlusion. Our results suggest that interleukin-6 and interleukin-8 may play important roles in the pathogenesis of this disease. This is the first report to describe the role of cytokines in this condition and relevant literature is reviewed. Our findings may lead to better understanding of the pathogenesis of M. pneumoniae-associated striatal lesions.

Bilateral Basal Ganglia Lesion after Glufosinate Ammonium (BASTA&amp;lt;sup&amp;gt;®&amp;lt;/sup&amp;gt;) Intoxication

Background: Glufosinate ammonium (Basta®) was developed in Japan in 1994 and was introduced to Korea as a non-selective herbicide. Recently, there is increasing concern about the glufosinate ammonium (GLA) intoxication. Case Report: We report a bilateral basal ganglia lesion that developed after Basta® ingestion. Hippocampal cytotoxic edema is usually encountered after GLA intoxication because profound hypotension or prolonged generalized tonic clonic seizures are usually accompanied. However, profound hypotensive episode or elevated creatine kinase was not observed during the hospital admission. After conservative ventilator support and antibiotic care for aspiration pneumonia, the patient was discharged to a chronic care facility. Conclusion: Bilateral striatal lesion except hippocampal involvement is one of the features of GLA intoxication. Toxic properties for GLA and other additives in Basta® should be thoroughly investigated. J Neurocrit Care 2014;7(2):125-128

Exercise training reinstates cortico-cortical sensorimotor functional connectivity following striatal lesioning: development and application of a subregional-level analytic toolbox for perfusion autoradiographs of the rat brain.

Current rodent connectome projects are revealing brain structural connectivity with unprecedented resolution and completeness. How subregional structural connectivity relates to subregional functional interactions is an emerging research topic. We describe a method for standardized, mesoscopic-level data sampling from autoradiographic coronal sections of the rat brain, and for correlation-based analysis and intuitive display of cortico-cortical functional connectivity (FC) on a flattened cortical map. A graphic user interface “Cx-2D” allows for the display of significant correlations of individual regions-of-interest, as well as graph theoretical metrics across the cortex. Cx-2D was tested on an autoradiographic data set of cerebral blood flow (CBF) of rats that had undergone bilateral striatal lesions, followed by 4 weeks of aerobic exercise training or no exercise. Effects of lesioning and exercise on cortico-cortical FC were examined during a locomotor challenge in this rat model of Parkinsonism. Subregional FC analysis revealed a rich functional reorganization of the brain in response to lesioning and exercise that was not apparent in a standard analysis focused on CBF of isolated brain regions. Lesioned rats showed diminished degree centrality of lateral primary motor cortex, as well as neighboring somatosensory cortex—changes that were substantially reversed in lesioned rats following exercise training. Seed analysis revealed that exercise increased positive correlations in motor and somatosensory cortex, with little effect in non-sensorimotor regions such as visual, auditory, and piriform cortex. The current analysis revealed that exercise partially reinstated sensorimotor FC lost following dopaminergic deafferentation. Cx-2D allows for standardized data sampling from images of brain slices, as well as analysis and display of cortico-cortical FC in the rat cerebral cortex with potential applications in a variety of autoradiographic and histologic studies.

Bilateral striatal lesions in a family with mitochondrial 14459G&gt;A mutation

Bilateral striatal lesions in a family with mitochondrial 14459G&gt;A mutation

N01 Cell Transplantation In Huntington's Disease

<h3>Introduction</h3> Cell transplantation is becoming a viable therapy for patients with Huntington’s disease (HD). Studies using rodent models of HD have identified a need for extended behavioural training to allow the recipient to ‘learn to use the graft’. Thus, after intra-striatal grafting of foetal tissue, striatally-dependent behaviours need to be re-established through targeted training. <h3>Aims</h3> To determine the extent to which cell transplantation can alleviate a range of cognitive deficits in rodent models of HD, and to identify the optimal parameters for successful alleviation of deficits. To develop a functional motor assessment in HD patients, that sensitively capture improvements in motor function that manifest post-transplantation. <h3>Method</h3> Rats will be pre-trained on a cognitive operant task that relies on the medial striatum. After receiving bilateral striatal lesions, a subset will be grafted with foetal ganglionic eminence. Thereafter, rats will be re-tested on the task at either 2 or 12 weeks post-graft to determine the optimal time to commence cognitive training. In HD patients, a range of motor tasks will be assessed to identify the items most sensitive to HD pathology. From this, a unique assessment tool will be developed that can sensitively measure improvements in motor function following cell transplantation. <h3>Results</h3> Results from the rat models of HD will help us understand the extent to which intra-striatal grafts can support cognitive and motor deficits, as well as revealing the optimal parameters for efficient use of the therapeutic intervention. Studies from patients with HD will help us to monitor the impact of the cell transplantation therapy through the development of a sensitive motor assessment. <h3>Conclusion</h3> Understanding the optimal parameters for efficient grafting and being able to sensitively monitor any improvement in function, due to graft integration, is critical to our development of cell replacement therapies and will help us move this treatment to clinical application.

Case 2: A teenager with nausea, vomiting and dysarthria

A 13-year-old boy presented with a five-month history of nausea and morning vomiting not associated with headaches or abdominal pains. His bowel movements were normal. He had demonstrated weight loss and reported fatigue, drooling, choking and bilateral calf muscle cramps. There were no visual changes, ataxia, vertigo, rigidity, seizures or psychiatric disturbances. His neurological examination was significant for tongue fasiculations, dysarthria, and mild weakness and tremor in the right hand, with poor coordination. The remainder of his neurological examination was normal, with no papilloedema. The differential diagnosis included central nervous system neoplasia, a demyelinating disease, a neurodegenerative disease, a metabolic disorder and a bradykinetic movement disorder such as juvenile Parkinsonism. Other considerations included drug effects or toxicity, and endocrine disorders such as hyperthyroidism. An urgent brain magnetic resonance imaging was scheduled. His thyroid profile, drug screen, electrolyte levels and renal function were all normal. Magnetic resonance imaging demonstrated bilateral symmetrical striatal and tegmental lesions suggestive of necrosis and/or calcifications (Figure 1). There was diffuse brain atrophy with prominent ventricles, wide occipital horns and prominent pericerebral spaces. Figure 1) Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging through the basal ganglia. Markedly increased FLAIR signal in the lentiform nuclei and caudate heads bilaterally, as well as the superimposed low signal, likely indicate mineralization ...

Progressive striatal necrosis associated with anti-NMDA receptor antibodies

BackgroundWe report a case of childhood onset, generalized dystonia due to slowly progressive bilateral striatal necrosis associated with anti-N-methyl-D-aspartate receptor (NMDAR) antibodies. This clinical phenotype has not been previously associated with NMDA receptor autoimmunity.Case presentationAn eighteen year old man presented with a history of childhood-onset, progressive generalized dystonia. Clinical examination revealed a pure generalized dystonia with no cognitive or other neurological findings. Magnetic resonance imaging showed bilateral high T2 signal striatal lesions, which were slowly progressive over a period of nine years. New parts of the lesion showed restricted water diffusion suggesting cytotoxic oedema. Positron emission tomography of the brain showed frontal hypermetabolism and cerebellar hypometabolism. Antibodies against the NR1 subunit of the NMDA receptor were detected in the patient’s serum and cerebrospinal fluid. There was no neoplasia or preceding infection or vaccination.ConclusionThis is the first report of chronic progressive bilateral striatal necrosis associated with anti-NMDAR antibodies. Our findings expand the clinical spectrum of disease associated with anti-NMDAR antibodies and suggest that these should be included in the work-up of dystonia with striatal necrosis.

Continuous reversal using internal or external cues: A novel test measuring set shifting in Parkinsonian rats

Parkinson’s disease (PD) is a predominant movement disorder, but profound cognitive deficits (e.g. bradyphrenia, memory, and set shifting) also occur. To model the deficits in set shifting using internal and external cues in rats we developed a continuous reversal task in which the active lever, left or right lever, alternated after a variable number of lever presses. In one task the active lever was signaled by a light (external cue condition, EC) whereas in the other task the active lever was not signaled (internal cue condition, IC). In this study we evaluated the effects of a partial bilateral striatal 6-OHDA lesion as model for PD on the performance in both tasks. Following behavioral testing the lesions were verified using tyrosine hydroxylase (TH) immunohistochemistry. The 6-OHDA lesioned animals were specifically impaired in the IC condition and not in the EC task. In other words, the lesioned animals kept pressing a lever longer although it was not longer active. The present response switching task is sensitive to 6-OHDA lesions and may mimic set-shifting deficits in PD. J. Exp. Clin. Med., 2012; 29:183-186

Defining the pathogenesis of human mtDNA mutations using a yeast model: The case of T8851C

More and more mutations are found in the mitochondrial DNA of various patients but ascertaining their pathogenesis is often difficult. Due to the conservation of mitochondrial function from yeast to humans, the unique ability of yeast to survive without production of ATP by oxidative phosphorylation, and the amenability of the yeast mitochondrial genome to site-directed mutagenesis, yeast is an excellent model for investigating the consequences of specific human mtDNA mutations. Here we report the construction of a yeast model of a point mutation (T8851C) in the mitochondrially-encoded subunit a/6 of the ATP synthase that has been associated with bilateral striatal lesions, a group of rare human neurological disorders characterized by symmetric degeneration of the corpus striatum. The biochemical consequences of this mutation are unknown. The T8851C yeast displayed a very slow growth phenotype on non-fermentable carbon sources, both at 28°C (the optimal temperature for yeast growth) and at 36°C. Mitochondria from T8851C yeast grown in galactose at 28°C showed a 60% deficit in ATP production. When grown at 36°C the rate of ATP synthesis was below 5% that of the wild-type, indicating that heat renders the mutation much more deleterious. At both growth temperatures, the mutant F1Fo complex was correctly assembled but had only very weak ATPase activity (about 10% that of the control), both in mitochondria and after purification. These findings indicate that a block in the proton-translocating domain of the ATP synthase is the primary cause of the neurological disorder in the patients carrying the T8851C mutation.This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.

The effect of Ginkgo biloba extract on 3-nitropropionic acid-induced neurotoxicity in rats

3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase enzyme (SDH), induces neurodegeneration similar to that observed in Huntington’s disease (HD). Reduction of prepulse inhibition (PPI) of acoustic startle response, locomotor hypoactivity, bilateral striatal lesions as well as brain oxidative stress are major features of HD. The present study was designed to investigate neuroprotective effect of Ginkgo biloba extract (EGb 761) on 3-NP induced neurobehavioral changes and striatal lesions. Rats administered 3-NP (20 mg/kg, s.c.) for five consecutive days exhibited PPI deficits and locomotor hypoactivity whereas, pretreatment of animals with EGb 761 (100 mg/kg, i.p. for 15 days) ahead of and during the induction of HD by 3-NP (20 mg/kg for 5 days starting at day 8) ameliorated 3-NP-induced neurobehavioral deficits. Administration of 3-NP increased the level of striatal malondialdehyde (MDA). This effect was prevented in animals pre-treated with EGb 761. Changes in the level of apoptotic regulatory gene expressions, following 3-NP treatment, were demonstrated as both an up-regulation and a down-regulation of the expression levels of striatal Bax and Bcl-xl genes, respectively. In addition, an up-regulation of the expression level of striatal glyceraldehyde-3-phosphate dehydrogenase ( GAPDH) was also observed. Pre-treatment with EGb 761 caused a down-regulation in striatal GAPDH and Bax together with an up-regulation of striatal Bcl-xl expression level as compared to the 3-NP treated group. Histochemical examination of striatal tissue showed that EGb 761 significantly prevented 3-NP induced inhibition of SDH activity. Histopathological examination further affirmed the neuroprotective effect of EGb 761 against 3-NP toxicity. Taken together, these results suggest that EGb 761 has a neuroprotective role in the current HD paradigm, which may be related to improvement of energy metabolism, antioxidant properties and antiapoptotic effects.

Bilateral striatal lesions disrupt performance in an operant delayed reinforcement task in rats

In order to provide an animal model of the impulsivity observed in Huntington's disease, the effects of bilateral neostriatal lesions in rats were evaluated in an operant delayed reinforcement task. When given a choice between responding to one lever for a small but immediate reward and a second lever for a larger delayed reward, normal rats exhibit a marked preference for responding to the high reward lever when the imposed delay is short, but progressively choose the lever associated with immediate small reward as the delays increase. Following striatal lesions, the animals continue to express similar preferences, but the lesions initially impose a distinct flattening of the delay-preference function, suggesting a relative insensitivity to the increasing delay parameter in making their response choices. However, this deficit declines with extend retraining on the task, such that 1-2 months after lesion the delay-dependent shift of preference from the delayed to the immediate lever as the delays lengthened was comparable in lesion and sham animals. Amphetamine further disinhibited all animals, apparent as a further increase in the number and reduction of the latencies of responses made to the lever associated with immediate reward. Striatal lesions had little influence on the effects of amphetamine on task performance, other than the increase in the numbers of omissions of lever and panel responses induced by the drug was more marked in the lesion than sham animals, and the lesioned animals exhibited less delay-dependency than the controls in their preference for responding to the lever associated with the larger delayed reinforcement at the highest (1.5 mg/kg) dose tested. The present results indicate small but clear effects of dorsal striatal lesions in an operant delayed reinforcement task, suggestive of an initial impairment in response selection and a reduction in their sensitivity to the delay interval itself. This deficit recovered with further training, which may be dependent upon relearning choice response procedures disrupted by the lesion, but might be reinstated by treatment with stimulant drugs. This article is part of a special issue entitled 'Behavioural, Anatomical, and Genetic Characterisation of Mouse and Rat Models of Huntington's Disease.'

A novel extended sequence learning task (ESLeT) for rodents: Validation and the effects of amphetamine, scopolamine and striatal lesions

Neurodegenerative diseases of the basal ganglia have been associated with impairments in 'implicit learning', failing to detect repeated sequences embedded in long series of random stimuli. The present study has introduced a novel 5-step sequence learning task (ESLeT) for rats, in which the animals learn to respond to randomly occurring stimuli in a horizontal spatial array, and to chain 5 sequential stimulus-response choices to gain food reward. The rats exhibit improved performance in both speed and accuracy of responding when the sequence is predictable following the first stimulus in the chain, suggesting a comparable capacity for 'implicit learning'. Performance was more rapid but less accurate when the rats were pre-treated with the dopamine indirect agonist amphetamine, markedly disrupted in both dependent variables when pre-treated with the cholinergic antagonist, scopolamine, and modestly disrupted following bilateral striatal lesions, with distinctive patterns of error and changes in the precise patterns of stimulus-by-stimulus responding associated with each experimental treatment. The ESLeT task provides a new test with distinctive advantages for the analysis of vigilance, serial responding and procedural motor learning in animal models of human neurodegenerative disease.

Time-dependent striatal dopamine depletion after injection of 6-hydroxydopamine in the rat. Comparison of single bilateral and double bilateral lesions.

For future investigation of possible perturbation of circadian rhythm in animal models of Parkinson's disease we needed an animal model providing lasting 80-100% striatal dopaminergic depletion in rats, but without induced mortality. We have thus compared the effects of a single hydroxydopamine bilateral striatal lesion (SB-hydroxydopamine) with those of a double hydroxydopamine bilateral lesion (DB-hydroxydopamine) at the same dose (16 microg/striatum) by HPLC determination of dopamine and 3,4-dihydrophenylacetic acid (dopac) levels in the striatum. Two weeks after neurosurgery, SB-hydroxydopamine and DB-hydroxydopamine induced dopaminergic depletion of at least 81% compared with control groups. After eight weeks striatal dopaminergic depletion was only 60.97% in SB-hydroxydopamine rats, suggesting a compensatory phenomenon, whereas in DB-hydroxydopamine rats dopaminergic loss was stable at 88%. For the DB-hydroxydopamine group the dopac/dopamine ratio was significantly increased at week 2 only, whereas no significant change was observed for other groups. This increase might be explained by increased dopamine turnover. We have demonstrated that striatal DB-hydroxydopamine injection induces lasting 80-100% neuronal loss, close to that observed in the disease in man, without induced mortality, and provides a tool which meets our experimental requirements.

Mutant SOD1 G93A in bone marrow-derived cells exacerbates 3-nitropropionic acid induced striatal damage in mice

3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, produces selective lesions in striatal neurons that resemble those observed in Huntington's disease neuropathology. In this study, we evaluated the role of peripheral bone marrow-derived cells (BMDCs) in the 3-NP-induced striatal damage by transplanting bone marrow cells with human SOD1 G93A mutation (mSOD1 G93A) which induces amyotrophic lateral sclerosis through an unknown gain of toxicity and mitochondrial dysfunction. We assessed striatal damage after 3-NP treatment in the recipient C57BL/6 wild-type (WT) mice that received bone marrow cells from WT or mSOD1 G93A transgenic donor mice (WT → WT or mSOD G93A → WT). After intraperitoneal injection of 3-NP, six of the eight mSOD1 G93A → WT mice had bilateral striatal lesions while only one out of eight WT → WT mice had a striatal lesion. The lesion volume was significantly higher in the mSOD1 G93A → WT mice than in the WT → WT mice. However, following an intrastriatal injection of 3-NP, there was no significant difference in the lesion volumes between the WT → WT mice and mSOD1 G93A → WT mice. Thus, the exacerbation of 3-NP-induced striatal damage in mSOD G93A → WT mice was only seen after systemic administration of 3-NP, but not after intrastriatal injection. These results demonstrate that altered SOD1 activity (mSOD G93A) in BMDCs affects striatal damage probably through a mechanism involving a systemic factor.